To elucidate the mechanism of insulin's anticatabolic effect in humans, protein dynamics were evaluated in the wholebody, splanchnic, and leg tissues in six C-peptide-negative type I diabetic male patients in the insulin-deprived and insulin-treated states using two separate amino acid models (leucine and phenylalanine). L-(1-3C,'5N)leucine, L-(ring-2H5)phenylalanine, and L-(ring-2H2) tyrosine were infused intravenously, and isotopic enrichments of [1-3C, 5N]-leucine, (13C)leucine, ("3C)ketoisocaproate, (2H5)phenylalanine, [21H4] tyrosine, (2H2)tyrosine, and '3CO2 were measured in arterial, hepatic vein, and femoral vein samples.Whole-body leucine flux, phenylalanine flux, and tyrosine flux were decreased (< 0.01) by insulin treatment, indicating an inhibition of protein breakdown. Moreover, insulin decreased (< 0.05) the rates of leucine oxidation and leucine transamination (P < 0.01), but the percent rate of ketoisocaproate oxidation was increased by insulin (P < 0.01). Insulin also reduced (< 0.01) whole-body protein synthesis estimated from both the leucine model (nonoxidative leucine disposal) and the phenylalanine model (disposal of phenylalanine not accounted by its conversion to tyrosine). Regional studies demonstrated that changes in whole body protein breakdown are accounted for by changes in both splanchnic and leg tissues. The changes in whole-body protein synthesis were not associated with changes in skeletal muscle (leg) protein synthesis but could be accounted for by the splanchnic region. We conclude that though insulin decreases whole-body protein breakdown in patients with type I diabetes by inhibition of protein breakdown in splanchnic and leg tissues, it selectively decreases protein synthesis in splanchnic tissues, which accounted for the observed decrease in whole-body protein synthesis. Insulin also augmented anabolism by decreasing leucine transamination. (J. Clin. Invest. 1995. 95:2926-2937

Insulin-like growth factors (IGFs) circulate attached to binding proteins (IGFBPs). Only the unbound form of IGF is suggested to be biological active. The main source of circulating IGF-I and IGFBP-1 is considered to be the liver, but that of circulating IGFBP-3 is not known. IGF-I and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. The aim of the present study was to examine the effect of insulin on the hepatic secretion of IGFBP-1, IGFBP-3, and IGF-I. Seven insulin-dependent diabetic patients in whom insulin was withheld for 12 h were studied in the overnight fasted state. Blood was sampled simultaneously from the hepatic vein, a peripheral vein, and an artery before and during insulin infusion for 3 h. The basal IGFBP-1 levels in the peripheral vein were several-fold elevated (249 +/- 44 micrograms/L) compared to those in healthy subjects (37 +/- 2 micrograms/L). Fasting IGFBP-1 concentrations were inversely correlated to the insulin levels (r = -0.918; P < 0.001). The mean IGF-I concentration (175 +/- 17 micrograms/L; -1.62 +/- 0.38 SD score) was decreased compared with that in age-matched healthy subjects. The basal IGFBP-3 levels in the peripheral vein (4.50 +/- 0.33 mg/L) were within the normal range. There was a significant correlation in the hepatic vein between fasting IGF-I and IGFBP-3 levels (r = 0.928; P < 0.001). Basal splanchnic IGFBP-1 production was 18 +/- 7 micrograms/min, whereas no basal net exchanges of IGF-I or IGFBP-3 were observed across the splanchnic area. Insulin inhibited splanchnic IGFBP-1 production within 120 min and glucose output within 20 min. Serum IGF-I, but not IGFBP-3, concentrations increased significantly during the insulin infusion. In summary, this study demonstrates the existence of considerable IGFBP-1 production from the liver during insulinopenia and the complete blocking of splanchnic IGFBP-1 production and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels. Thus, insulin may play a role in determining the bioavailability of IGF-I.

These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

OBJECTIVE -To evaluate whether treatment with insulin in recently diagnosed type 2 diabetes is advantageous compared with glibenclamide treatment. RESEARCH DESIGN AND METHODS-␤-Cell function, glycemic control, and quality of life were monitored over 2 years in 39 patients with islet cell antibody-negative type 2 diabetes diagnosed 0 -2 years before inclusion in a Swedish multicenter randomized clinical trial. Patients were randomized to either two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide (3.5-10.5 mg daily). C-peptide-glucagon tests were performed yearly in duplicate after 2-3 days of temporary withdrawal of treatment. RESULTS-After 1 year the glucagon-stimulated C-peptide response was increased in the insulin-treated group by 0.14 Ϯ 0.08 nmol/l, whereas it was decreased by 0.12 Ϯ 0.08 nmol/l in the glibenclamide group, P Ͻ 0.02 for difference between groups. After 2 years, fasting insulin levels were higher after treatment withdrawal in the insulin-treated versus the glibenclamidetreated group (P ϭ 0.02). HbA 1c levels decreased significantly during the first year in both groups; however, at the end of the second year, HbA 1c had deteriorated in the glibenclamide group (P Ͻ 0.01), but not in the insulin-treated group. The difference in evolution of HbA 1c during the second year was significant between groups, P Ͻ 0.02. A questionnaire indicated no difference in well-being related to treatment.CONCLUSIONS -Early insulin versus glibenclamide treatment in type 2 diabetes temporarily prolongs endogenous insulin secretion and promotes better metabolic control. Diabetes Care 26:2231-2237, 2003I n type 2 diabetes, metabolic control deteriorates in most patients when the duration of diabetes increases (1). Decreased insulin secretion likely explains this deterioration in metabolic control (1,2). Decreased insulin secretion could be due to excessive secretory demands on the ␤-cells (1). If so, insulin treatment would be beneficial by providing relative "␤-cell rest." However, sulfonylurea drugs may exert negative effects by overstimulating ␤-cells. No studies, to our knowledge, have been performed that rigorously compare the effects of sulfonylurea versus insulin treatment on the deterioration of insulin secretion in type 2 diabetic patients. The U.K. Prospective Diabetes Study (UKPDS) (1) randomized patients at inclusion to insulin or sulfonylurea and documented a deterioration of insulin secretion after sulfonylurea; however, endogenous insulin secretion in the insulin-treated group was not evaluated due to ongoing insulin treatment.The main aim of this prospective study was to examine whether insulin versus glibenclamide treatment started soon after the diagnosis of type 2 diabetes is associated with better ␤-cell function. We furthermore tested whether the two treatments affected differently metabolic control and other clinically relevant parameters. We studied patients with recent onset of type 2 diabetes, after excluding latent autoimmune diabetes in adults (LADA) (3). RESEARCH...

In order to determine the possible influence of C-peptide on nerve function, 12 insulin-dependent diabetic (IDDM) patients with symptoms of diabetic polyneuropathy were studied twice under euglycaemic conditions. Tests of autonomic nerve function (respiratory heart rate variability, acceleration and brake index during tilting), quantitative sensory threshold determinations, nerve conduction studies and clinical neurological examination were carried out before and during a 3-h i.v. infusion of either C-peptide (6 pmol.kg-1.min-1) or physiological saline solution in a double-blind study. Plasma C-peptide concentrations increased from 0.11 +/- 0.02 to 1.73 +/- 0.04 nmol/l during C-peptide infusion. Clinical neurological examination quantitative sensory threshold evaluations and nerve conduction measurements failed to detect significant changes between C-peptide and saline study periods. Respiratory heart rate variability increased significantly from 13 +/- 1 to 20 +/- 2% during C-peptide infusion (p < 0.001), reaching normal values in five of the subjects; control studies with saline infusion did not alter the heart rate variability (basal, 14 +/- 2; saline, 15 +/- 2%). A reduced brake index value was found in seven patients and increased significantly during the C-peptide infusion period (4.6 +/- 1.0 to 10.3 +/- 2.2%, p < 0.05) but not during saline infusion (5.9 +/- 2 to 4.1 +/- 1.1%, NS). It is concluded that short-term (3-h) infusion of C-peptide in physiological amounts may improve autonomic nerve function in patients with IDDM.